Master's Theseshttp://hdl.handle.net/2022/31842018-05-24T17:53:36Z2018-05-24T17:53:36ZDesign of Peptide-Based Prodrug Chemistry and Its Application to Glucagon-like Peptide IDe, Arnabhttp://hdl.handle.net/2022/31852008-08-26T19:00:19Z2007-01-01T00:00:00ZDesign of Peptide-Based Prodrug Chemistry and Its Application to Glucagon-like Peptide I
De, Arnab
Peptide-based drugs are highly effective medicines with relatively short duration of action and of variable therapeutic index. Glucagon-like peptide 1 is a hormone that offers promise in the treatment of Type II diabetes. However, the biggest problem in the therapeutic use of GLP-1 is its extremely short half-life in plasma (~2
min). A prodrug of GLP-1 should extend and improve the pharmacodynamics of this
peptide hormone. We have designed prodrugs that slowly convert to the parent drug at
physiological conditions of 37C and pH 7.2 driven by their inherent chemical instability
without the need of any enzymatic cleavage. We observed that amide prodrugs could not
convert to the active peptides under physiological conditions. Consequently, we decided to synthesize peptide drugs which had a hydroxy-terminal extension instead of a Nterminal amine. Ester prodrugs were prepared using these hydroxy-peptides as the
scaffold. We explored the diketopiperazine and diketomorpholine (DKP and DMP) strategy for the chemical flexibility that it offers to develop prodrugs with variable time
actions. The esters proved to be more labile than the corresponding amides and the
dynamic range in rate of cleavage ranged from an hour to almost half a week. We found
that the rate of cleavage depends on the structure and stereochemistry of the dipeptide pro-moiety and also on the strength of the nucleophile. The careful selection of appropriate functionality that balances chemical, biological and immunological features under physiological conditions has also been reported.
2007-01-01T00:00:00Z